The main objective of this research project is to genetically engineer immunoglobulin genes to study structure-function relationships and to generate potentially useful immunological reagents for diagnosis and therapy of human tumors. Several hybridoma cell lines have been developed in this laboratory that produce monoclonal antibodies (MAbs) with selective reactivity to various tumor types. These MAbs include those that recognize carcinoembryonic antigen, and a high molecular weight, mucin-like pancarcinoma antigen, TAG-72. The MAbs are currently being evaluated in a number of diagnostic and therapeutic trials on breast, colon and ovarian cancers. The murine MAbs, B72.3 and its second generation counterpart MAb CC49, which recognize TAG-72, have shown promise for being developed into diagnostic and therapeutic agents. A major impediment to the clinical application of murine MAbs is their potential to elicit human anti-mouse antibody (HAMA) response in some patients. This problem can be effectively minimized by genetically replacing the constant region of the mouse antibody with the constant region of human antibody as well as with other genetically engineered manipulations.